DE2915158C2 - 2-Hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether, process for its preparation and pharmaceuticals - Google Patents

2-Hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether, process for its preparation and pharmaceuticals

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Publication number
DE2915158C2
DE2915158C2 DE2915158A DE2915158A DE2915158C2 DE 2915158 C2 DE2915158 C2 DE 2915158C2 DE 2915158 A DE2915158 A DE 2915158A DE 2915158 A DE2915158 A DE 2915158A DE 2915158 C2 DE2915158 C2 DE 2915158C2
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DE
Germany
Prior art keywords
indazol
benzyl
dimethylamine
hydroxy
propyl ether
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
DE2915158A
Other languages
German (de)
Other versions
DE2915158A1 (en
Inventor
Antonio Dr. Guadalajara Alcaide Garcia
Juan Dr. Madrid Bermejo Lozano
Juan Ramon Dr. Conde Ruiz
Jose Dr. Macias Hachuel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Liade SA
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Laboratorios Liade SA
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Filing date
Publication date
Application filed by Laboratorios Liade SA filed Critical Laboratorios Liade SA
Publication of DE2915158A1 publication Critical patent/DE2915158A1/en
Application granted granted Critical
Publication of DE2915158C2 publication Critical patent/DE2915158C2/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pain & Pain Management (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

2. Verfahren zur Herstellung des 2-Hydroxy-benzoats von 1 -Benzyl-1 H-indazol-3-yl-3-(dimethylamin)-propyläther nach Anspruch 1, dadurch gekennzeichnet, daß man eine alkoholische Lösung von 2-Hydroxy-benzoesäure und eine weitere Lösung von l-Benzyl-lH-indazol-3-yl-3-(dimethylamin)-propyläther zum Rückfluß bringt.2. Process for the preparation of the 2-hydroxy-benzoate from 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether according to claim 1, characterized in that one alcoholic solution of 2-hydroxy-benzoic acid and another Bringing solution of l-benzyl-lH-indazol-3-yl-3- (dimethylamine) propyl ether to reflux.

3. Arzneimittel, enthaltend die Verbindung nach Anspruch 1, gegebenenfalls zusammen mit üblichen Trägern und Hilfsmitteln.3. Medicaments containing the compound according to claim 1, optionally together with customary Carriers and aids.

4. Arzneimittel nach Anspruch 3 in zur topischen Anwendung geeigneter Form.4. Medicament according to claim 3 in a form suitable for topical use.

1010

1515th

2020th

2525th

CH3 CH 3

coocoo

nol, zugetropft werden. Man erwärmt weitere 2 Stunden unter Rückfluß. Am Ende dieser Zeit läßt man das Gemisch in einem Kühlschrank während 12 Stunden auf O0C kühlen.nol, to be added dropwise. The mixture is refluxed for a further 2 hours. At the end of this time, the mixture is allowed to cool to 0 ° C. in a refrigerator for 12 hours.

Die Kristalle werden abfiltriert und mit Äthanol bei 00C gewaschen und auf Filterpapier getrocknet Man erhält 180 g o-Hydroxybenzoat von 1-Benzyl-lH-indazol-3-yl-3-(dimethylamino)-propyläther. The crystals are filtered and washed with ethanol at 0 0 C and dried on filter paper are obtained 180 g of o-hydroxybenzoate 1-Benzyl-lH-indazol-3-yl-3- (dimethylamino) -propyläther.

Im folgenden wird die erfindungsgemäße Verbindung abgekürzt wiedergegeben als LIA-1032.In the following, the compound according to the invention is abbreviated as LIA-1032.

Versuchstiere wurden auf die Wirkung von 6% LIA-1032 bei lokaler Anwendung gegenüber Schmerzen, erzeugt durch chemische und elektrische Stimuli, gegen Entzündungen (Plantarödeme, hervorgerufen durch Kaolin, Kontaktödeme, hervorgerufen durch Crotonöl) und auf die Kapillar-Permeabilität untersucht. Als Vergleichsprodukt wurde eine Lösung von Benzydamin-hydrochlorid in einer molekularen Konzentration gleich der von LIA-1032 verwendet.Test animals were tested for the effect of 6% LIA-1032 when applied locally against pain, generated by chemical and electrical stimuli, against inflammation (plantar edema, caused kaolin, contact edema caused by croton oil) and examined for capillary permeability. A solution of benzydamine hydrochloride was used as a comparative product used at a molecular concentration equal to that of LIA-1032.

Die Ergebnisse der Schmelzuntersuchung, induziert durch chemischen Stimulus (Essigsäure-Intraperitoneal, »Whiting Test«, Methode von Koster, modifiziert durch Witkin und Mitarbeiter, Maus) sind in der Tabelle I aufgeführt.The results of the enamel examination, induced by chemical stimulus (acetic acid intraperitoneal, "Whiting Test", Koster method, modified by Witkin and coworkers, Maus) are listed in Table I.

Tabelle ITable I.

Produktproduct

Die Erfindung betrifft das 2-Hydroxy-benzoat des 1 -Benzyl-1 H-indazol-3-yl-3-(dimethylamin)-propyläthers der FormelThe invention relates to the 2-hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether the formula

35 Zeit 35 time

Analgesie-Ausmaß Degree of analgesia

30 LIA-1032 30 LIA-1032

Benzydamin · HClBenzydamine · HCl

5'
10'
30'5 '
10 '
30 '

5'
10'
30'5 '
10 '
30 '

58% 60% 54%58% 60% 54%

45% 38% 19%45% 38% 19%

das pharmakologisch wirksam ist.which is pharmacologically effective.

Bei der Verbindung handelt es sich um ein stabiles The connection is stable

weißes kristallines Pulver, dessen Schmelzpunkt bei 45 produkt 94-96° C liegt.white crystalline powder, the melting point of which is 45 product 94-96 ° C.

Die erfindungsgemäße Verbindung stellt man her The compound according to the invention is produced

durch Reaktion einer alkoholischen Lösung von 2-Hydroxy-benzoesäure mit einer weiteren alkoholischen Lösung von 1 -Benzyl- lH-indazol-3-yl-3-(dimethylamin)-propyläther. by reaction of an alcoholic solution of 2-hydroxy-benzoic acid with another alcoholic solution Solution of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether.

Die erfindungsgemäße Verbindung weist pharmakologische Eigenschaften auf. Sie besitzt insbesondere lokale und revulsive entzündungshemmende bzw. anti-inflammatorische Eigenschaften, wowohl bei Versuchstieren, als auch beim Menschen. Sie weist therapeutische, analgetische und anti-inflammatorische Wirkungen, beispielsweise bei geschlossenen traumatischen Verletzungen auf.The compound according to the invention has pharmacological properties. She in particular owns local and revulsive anti-inflammatory or anti-inflammatory properties, both in experimental animals, as well as in humans. It has therapeutic, analgesic and anti-inflammatory Effects, for example in closed traumatic injuries.

Die Ergebnisse bei elektrischem Stimulus (Mäuseschwanz, Radouco-Thomas-Methode) sind in der Tabelle II aufgeführt.The results with electrical stimulus (mouse tail, Radouco-Thomas method) are in the Table II listed.

Tabelle IITable II

ZeitTime

Analgesie-Ausmaß Degree of analgesia

LIA-1032LIA-1032

Benzydamin · HClBenzydamine · HCl

5'
10'
30'5 '
10 '
30 '

5'
10'
30'5 '
10 '
30 '

40% 50% 70%40% 50% 70%

50% 50% 30%50% 50% 30%

Plantarödem, induziert durch Kaolin am Fuß einer Ratte (Wilhem- und Domenjoz-Methode) wurde beträchtlich inhibiert, und die Wirkung war andauernd (vgl. Tabelle III).Plantar edema induced by kaolin on the foot of a rat (Wilhem and Domenjoz method) became considerable inhibited and the effect was sustained (see Table III).

Beispielexample

In einen 21 Destillations-Rundkolben mit zwei öffnungen, ausgerüstet mit einem Rückflußkühler und einem Trichter mit Hahn werden 69 g (0,5 Mol) 2-Hydroxy-benzoesäure in 500 ml Äthanol gelöst. Das Gemisch wird zum Rückfluß gebracht, während aus dem Tropftrichter 155 g (0,5 Mol) l-Benzyl-lH-indazol-3-yl-3-(dimethylamin)-propyläther, gelöst in 100 ecm Ätha-Into a 21 distillation round bottom flask with two openings, equipped with a reflux condenser and a funnel with a tap, 69 g (0.5 mol) 2-Hydroxy-benzoic acid dissolved in 500 ml of ethanol. The mixture is brought to reflux while leaving the Dropping funnel 155 g (0.5 mol) of l-benzyl-lH-indazol-3-yl-3- (dimethylamine) propyl ether, dissolved in 100 ecm etha

6060

Tabelle IIITable III

Verbindunglink

lnhibierungs-AusmaßDegree of inhibition

IStd. 2Std. 3Std. 4Std. 5Std.IStd. 2 hours. 3 hours. 4h 5h

LIA-1032 33% 32% 51% 39% 48%LIA-1032 33% 32% 51% 39% 48%

Benzydamin · HCI 48% 22% 34% 20% 8%Benzydamine HCI 48% 22% 34% 20% 8%

Im Falle des durch Crotonöl hervorgerufenen Kontaktödems (Ratte, modifizierte Selye-Methode) war der entzündungshemmende Effekt fast noch ausgeprägter und wesentlich intensiver, als der der Vergleichsverbindung (vgl. Tabelle IV).In the case of contact edema caused by croton oil (rat, modified Selye method) the anti-inflammatory effect is almost more pronounced and much more intense than that of the comparison compound (see Table IV).

Tabelle IVTable IV Menge derAmount of Inhibierungs-Inhibition Verbindunglink Verbindung proConnection per Ausmaßextent ml Crotonölml of croton oil ImIImI 91%91% LIA-1032LIA-1032 0,5 ml0.5 ml 95%95% 0,25 ml0.25 ml 96%96% ImIImI 40%40% Benzydamin ■ HClBenzydamine ■ HCl 0,5 ml0.5 ml 26%26% 0,25 ml0.25 ml 0%0%

Die Tabelle V zeigt die Modifizierungen, die bei der Kapillar-Permeabilität an der enthaarten Abdomenhaut des Kaninchens erhalten wurde (nach der modifizierten Willoughby-Methode). Die Permeabilität wurde sowohl am normalen Tier, als auch am gleichzeitig mit einemTable V shows the modifications made in capillary permeability to the depilated abdominal skin of the rabbit (modified by Willoughby's method). The permeability was both on the normal animal, as well as on the same time as one

Tabelle VTable V

Reizmittel, wie Chloroform, behandelten Tier untersucht Es ist ersichtlich, daß LIA-1032 die Kapillar-Permeabilität kaum ändert und darüber hinaus die aurch Chloroform bewirkte Permeabilitätszunahme verringert. Irritants, such as chloroform, were examined in the treated animal It can be seen that LIA-1032 hardly changes the capillary permeability and moreover the aurch The increase in permeability caused by chloroform is reduced.

Produktproduct

Zunahme der Kapillar-Permeabilität (%)Increase in capillary permeability (%)

V2 Std. 1 Std. 1V2 Std. 2 Std.V 2 hours 1 hour 1V 2 hours 2 hours

IV2 Std.IV 2 hours

3 Std.3 hours.

3V2 Std. 4S!d.3V 2 hours 4S! D.

00 00 00 00 00 00 00 00 2,52.5 2,52.5 2,52.5 2,52.5 7,57.5 7,57.5 00 00 00 00 00 00 00 00 00 00 5555 57,557.5 6060 6060 6060 6060 6060 6060 32,532.5 4545 4545 52,552.5 5050 5555 37,537.5 37.537.5

Vergleich
LIA-1032
Benzydamin · HCl
Chloroformcomparison
LIA-1032
Benzydamine · HCl
chloroform

LIA-1032 +
ChloroformLIA-1032 +
chloroform

Die Untersuchungen der lokalen Toleranz wurden am Tränenbildung während der ersten 24 Stunden, die inThe studies of local tolerance were based on tear formation during the first 24 hours in

beiden Fällen nach 96 Stunden völlig zurückgingen. Es wurden keine Geschwürbildungen oder Trübungen festgestellt.both cases receded completely after 96 hours. There were no ulcers or opacities established.

Die DL5C (Maus) des aktiven Prinzips betrug bei oraler Verabreichung 1772 mg/kg.The DL 5C (mouse) of the active principle when administered orally was 1772 mg / kg.

enthaarten Adomen und an der Bindehaut des Kaninchens durchgeführt. Es zeigten sich keine Hautänderungen nach dem Auftrag von LIA-1032; das Benzidamin · HCl erzeugte einen starken Blutstrom bei Anwendung in 17OnTi eines Druckverbands. Beide Präparate ergaben eine Rötung der Bindehäute unddepilated adomen and performed on the conjunctiva of the rabbit. There were no skin changes after the application of LIA-1032; the benzidamine · HCl created a strong blood flow when applied in 17 OnTi of a pressure bandage. Both preparations resulted in reddening of the conjunctiva and

4545

Claims (1)

Patentansprüche:Patent claims: 1. 2-Hydroxy-benzoat des l-Benzyl-lH-indazol-3-yl-3-(dimethylamin)-propyläthers der Formel1. 2-Hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether the formula CH3 CH 3 COO HN-CH3 COO HN-CH 3 OH (CHj)3-OOH (CHj) 3 -O
DE2915158A 1978-04-13 1979-04-12 2-Hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether, process for its preparation and pharmaceuticals Expired DE2915158C2 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
ES468785A ES468785A1 (en) 1978-04-13 1978-04-13 A 1-benzyl-1H-indazol-3-il-3- (dimethyl amine)-propyl ether derivative and a process of producing same

Publications (2)

Publication Number Publication Date
DE2915158A1 DE2915158A1 (en) 1979-10-25
DE2915158C2 true DE2915158C2 (en) 1981-10-29

Family

ID=8475837

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DE2915158A Expired DE2915158C2 (en) 1978-04-13 1979-04-12 2-Hydroxy-benzoate of 1-benzyl-1H-indazol-3-yl-3- (dimethylamine) propyl ether, process for its preparation and pharmaceuticals

Country Status (7)

Country Link
JP (1) JPS604828B2 (en)
BE (1) BE875513A (en)
DE (1) DE2915158C2 (en)
ES (1) ES468785A1 (en)
FR (1) FR2422642A1 (en)
GB (1) GB2024200B (en)
NL (1) NL7902892A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19800028A1 (en) * 1998-01-02 1999-07-22 Bosch Gmbh Robert LCD display with back-illumination

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19800028A1 (en) * 1998-01-02 1999-07-22 Bosch Gmbh Robert LCD display with back-illumination

Also Published As

Publication number Publication date
JPS54163572A (en) 1979-12-26
GB2024200B (en) 1982-07-14
JPS604828B2 (en) 1985-02-06
FR2422642A1 (en) 1979-11-09
BE875513A (en) 1979-07-31
FR2422642B1 (en) 1981-10-23
GB2024200A (en) 1980-01-09
ES468785A1 (en) 1978-11-16
NL7902892A (en) 1979-10-16
DE2915158A1 (en) 1979-10-25

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